Glioblastoma (GBM) is a highly aggressive, malignant, primary brain tumor. Despite state-of-the-art standard-of-care treatment (surgery, chemotherapy, radiation), GBM inevitably recurs, usually in the peritumoral irradiated tumor/brain interface within two centimeters of the margins of the resection cavity. Anti-PD-L1 (immune checkpoint) inhibitors represent an important new class of cancer treatments, but have shown little efficacy in GBM. In a mouse glioma model, we demonstrate that late evolving effects of radiation blunt the therapeutic effectiveness of anti-PD-L1. Carbogen/O2 gas challenge experiments in these mice six weeks post-irradiation demonstrate that the brain microenvironment is physiologically modified, consistent with the observed blunting of immunotherapy.